DESCRIPTION(From applicant's abstract): Our goal is to understand the decline in cholinergicneurotransmission associated with age and to determine if intervention with exogenous aaents such as cholinergic agonists or anti-inflammatories modifies this age-related process. The overall hypothesis to be tested is: Long-term oral administration of nicotine and/or non-steroidal anti-inflammatories to adult CBA/J mice provides protection against age-related loss and/or changes in nicotinic cholinergic receptor expression and function. We have developed a mouse model (Rogers et al., J. Neurosci. 18:4825-4832, 1998) that reliably reflects age-related decline in neuronal nicotinic acetylcholine receptor (nAChR) expression (i.e., nAChRa4 subunit) and shown that long-term (1 year) oral nicotine delivery slows this decline. No data are available regarding other nAChR subunit expression in the aging mouse brain, or how the brain may compensate for the changes. Notably, the nAChRa4 expressing cholinergic neurons in CAl that are diminished in the aged brain also constitutively express cyclooxygenase-2 (COX2), a target of non-steroidal anti-inflammatories (NSAIDs) that have been suggested to be neuroprotective. The focus of this proposal is to examine the influence of long-term (1-year) oral nicotine, Cox-2 preferring NSAIDs or both on the process of age-related change in nAChA expression and function in the CBA mouse brain through answering three basic questions. Specific Aim 1: Do age-related changes in the expression of multiple nicotinic acetyicholine receptor (nAChR) subunits occur and are these changes modified by long-term nicotine administration? Specific Aim 2: Does inhibition of cyclooxygenase 2 by non-steroidal anti-inflammatory drugs (NSA!Ds) impact age-related alterations in nAChR subunit expression? Finally, since aging influences many cellular functions including the ability to respond to inflammatory agents, we will ask in Specific Aim 3 using microarray chip analysis; Do these treatments contribute to maintaining normal transcriptional responses by the brain?